Evaluation of 4β‐Hydroxycholesterol as a Clinical Biomarker of CYP3A4 Drug Interactions Using a Bayesian Mechanism–Based Pharmacometric Model

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  • TA Leil
    Exploratory Clinical & Translational Research, Bristol‐Myers Squibb Company Lawrenceville New Jersey USA
  • S Kasichayanula
    Exploratory Clinical & Translational Research, Bristol‐Myers Squibb Company Lawrenceville New Jersey USA
  • DW Boulton
    Exploratory Clinical & Translational Research, Bristol‐Myers Squibb Company Lawrenceville New Jersey USA
  • F LaCreta
    Exploratory Clinical & Translational Research, Bristol‐Myers Squibb Company Lawrenceville New Jersey USA

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<jats:p>A Bayesian mechanism–based pharmacokinetic/pharmacodynamic model of cytochrome P450 3A4 (CYP3A4) activity was developed based on a clinical study of the effects of ketoconazole and rifampin on midazolam exposure and plasma 4β‐hydroxycholesterol (4βHC) concentrations. Simulations from the model demonstrated that the dynamic range of 4βHC as a biomarker of CYP3A4 induction or inhibition was narrower than that of midazolam; an inhibitor that increases midazolam area under the curve by 20‐fold may only result in a 20% decrease in 4βHC after 14 days of dosing. Likewise, an inducer that elevates CYP3A4 activity by 1.2‐fold would reduce the area under the curve of midazolam by 50% but would only increase 4βHC levels by 20% after 14 days of dosing. Elevation in 4βHC could be reliably detected with a twofold induction in CYP3A4 activity with study sample sizes (<jats:italic>N</jats:italic> ~ 6–20) typically used in early clinical development. Only a strong CYP3A4 inhibitor (e.g., ketoconazole) could be detected with similar sample sizes.</jats:p><jats:p><jats:italic>CPT Pharmacometrics Syst. Pharmacol</jats:italic>. (2014) 3, e120; doi:<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="doi" xlink:href="10.1038/psp.2014.18">10.1038/psp.2014.18</jats:ext-link>; published online 25 June 2014</jats:p>

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